Method for treatment of rosacea in patients aged 65 years and older

ABSTRACT

A regimen for the therapeutic treatment of rosacea in subjects aged 65 years and older, the regimen comprising topically applying to the skin of a subject aged 65 years and older in need of said treatment a pharmaceutical composition, the pharmaceutical composition comprising about 1% w/w to about 10% w/w benzoyl peroxide as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the benzoyl peroxide is the only active ingredient in said pharmaceutical composition, wherein said pharmaceutical composition is applied once daily for a period of at least about 2 weeks, to achieve, in a group of such subjects, a success rate of at least about 15%, wherein the success rate is defined as the number of subjects achieving clear or almost clear skin on the investor global assessment (IGA) scale after treatment with the pharmaceutical composition.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/794,839, filed Feb. 19, 2020, now U.S. Pat. No. 10,933,046, grantedMar. 2, 2021, which claims priority under 35 U.S.C. § 119(e) from U.S.Provisional Application No. 62/977,952, filed Feb. 18, 2020, U.S.Provisional Application No. 62/977,974, filed Feb. 18, 2020, U.S.Provisional Application No. 62/972,896, filed Feb. 11, 2020, U.S.Provisional Application No. 62/972,310, filed Feb. 10, 2020, U.S.Provisional Application No. 62/960,384, filed Jan. 13, 2020, U.S.Provisional Application No. 62/925,258, filed Oct. 24, 2019, U.S.Provisional 62/871,283, filed Jul. 8, 2019, U.S. Provisional 62/871,286,filed Jul. 8, 2019, U.S. Provisional 62/807,356, filed Feb. 19, 2019,and U.S. Provisional 62/807,368, filed Feb. 19, 2019, the contents ofwhich are incorporated in their entirety as if fully set forth herein.

TECHNICAL FIELD

This application relates to methods for the therapeutic treatment ofsymptoms and considerations associated with skin conditions andafflictions, such as rosacea, in patients aged 65 years and older,including topically applying to the skin of a subject in need of saidtreatment a pharmaceutical composition comprising benzoyl peroxide.

BACKGROUND

Rosacea is a chronic disease of inflammatory dermatitis that mainlyaffects the median part of the face and the eyelids of certain adults.It is characterized by telangiectatic erythema, dryness of the skin,papules and pustules. Conventionally, rosacea develops in adults fromthe ages of 30 to 50. Elderly patients who are above the age of 65, havegenerally fragile and sensitive skin (Stalder et al., “Fragility ofEpidermis and its Consequence in Dermatology, J. Eur. Acad. Dermatol.Venereol., 28 (s4), 1-18 (2014)), and when suffering from rosacea, haveadditional dysfunctional skin barrier which reflects the integrity ofthe epidermis (Blume-Peytavi et al., “Fragility of epidermis innewborns, children and adolescents, J. Eur. Acad. Dermatol. Venereol.,30 (s4), 3-56 (2016)), and therefore, treatment in rosacea in elderlypatients is more challenging. Women are more frequently affected byrosacea, although the condition is generally more severe in men. Rosaceais a primitively vascular condition whose inflammatory stage lacks thecysts and comedones characteristic of common acne.

Factors that have been described as possibly contributing towards thedevelopment of rosacea include, for example: the presence of parasitessuch as the Demodex folliculorum; the presence of bacteria such asHelicobacter pylori (a bacterium associated with gastrointestinaldisorders); hormonal factors (such as endocrine factors); climatic andimmunological factors; and so forth.

Rosacea develops in four stages over several years, in spasms aggravatedby variations in temperature, alcohol, spices, exposure to sunlight andstress. The various stages of the disease are:

Stage 1 (stage of erythema episodes): the patients have erythrosisspasms due to the sudden dilation of the arterioles of the face, whichthen take on a congestive, red appearance. These spasms are caused byemotions, meals and temperature changes.

Stage 2 (stage of couperosis, i.e., of permanent erythema withtelangiectasia): certain patients also have oedema on the cheeks and theforehead.

Stage 3 (inflammatory stage, papulopustular rosacea): patients exhibitappearance of inflammatory papules and pustules, but without affectingthe sebaceous follicles, and thus, does not include cysts and comedones.

Stage 4 (rhinophyma stage): this late phase essentially affects men. Thepatients have a bumpy, voluminous red nose with sebaceous hyperplasiaand fibrous reordering of the connective tissue.

Erythema is a symptom of rosacea, and includes an abnormal and/orsuperficial reddening and inflammation of the skin, usually localized orpatchy, caused by the congestion and dilation of blood capillaries.

Typical treatment of rosacea includes oral or topical administration ofantibiotics such as tetracyclines, salicylic acid, anti-fungal agents,steroids, metronidazole (an anti-bacterial agent) and isotretinoin, ortreatment with anti-infectious agents such as azelaic acid.

SUMMARY

An exemplary embodiment of this application is a regimen for thetherapeutic treatment of rosacea in subjects aged 65 years and older,the regimen comprising topically applying to the skin of a subject aged65 years and older in need of said treatment a pharmaceuticalcomposition, the pharmaceutical composition comprising about 1% w/w toabout 10% w/w benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is applied oncedaily for a period of at least about 2 weeks, to achieve, in a group ofsuch subjects, a success rate of at least about 15%, wherein the successrate is defined as the number of subjects achieving clear or almostclear skin on the investor global assessment (IGA) scale after treatmentwith the pharmaceutical composition.

In another exemplary embodiment, the success rate after about 2 weeks oftreatment is about 18%.

In another exemplary embodiment, the success rate of said regimen aftertreatment for about 2 weeks is at least about 10% greater than a successrate achieved by a vehicle control.

Another exemplary embodiment of this application is a regimen for thetherapeutic treatment of rosacea in a subject 65 years and older, theregimen comprising topically applying to the skin of a subject aged 65years and older in need of said treatment a pharmaceutical composition,the pharmaceutical composition comprising about 1% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, wherein saidpharmaceutical composition is applied once daily for a period of atleast about 4 weeks, to achieve, in a group of such subjects, a successrate of at least about 25%, wherein the success rate is defined as thenumber of subjects achieving clear or almost clear skin on the investorglobal assessment (IGA) scale after treatment with the pharmaceuticalcomposition.

In another exemplary embodiment, the success rate after about 4 weeks oftreatment is at least about 29%.

In another exemplary embodiment, the success rate of said regimen aftertreatment for about 4 weeks is at least about 2% greater than a successrate achieved by a vehicle control.

Another exemplary embodiment of this application is a regimen for thetherapeutic treatment of rosacea in a subject aged 65 years and older,the regimen comprising topically applying to the skin of the subjectaged 65 years and older in need of said treatment a pharmaceuticalcomposition, the pharmaceutical composition comprising about 1% w/w toabout 10% w/w benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is applied oncedaily for a period of at least about 8 weeks, to achieve, in a group ofsuch subjects, a success rate of at least about 45%, wherein the successrate is defined as the number of subjects achieving clear or almostclear skin on the investor global assessment (IGA) scale after treatmentwith the pharmaceutical composition.

In another exemplary embodiment, the success rate after about 8 weeks oftreatment is at least about 52%.

In another exemplary embodiment, the success rate of said regimen afterabout 8 weeks of treatment is at least about 20%, preferably at leastabout 27% greater than a success rate achieved by the vehicle control.

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 12 weeks, toachieve, in a group of such subjects, a success rate of at least about50%, wherein the success rate is defined as the number of subjectsachieving clear or almost clear skin on the investor global assessment(IGA) scale after treatment with the pharmaceutical composition.

In another exemplary embodiment, the success rate after treatment forabout 12 weeks is at least about 56%.

In another exemplary embodiment, the success rate of said regimen afterabout 12 weeks of treatment, is at least about 20%, preferably at leastabout 28% greater than the success rate achieved by the vehicle control.

Another exemplary embodiment is a pharmaceutical composition for use inthe treatment of severe rosacea in a subject 65 years and older, saidpharmaceutical composition comprising from about 1% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, and saidpharmaceutical composition is applied once daily for a period of atleast about 2 weeks, about 4 weeks, about 8 weeks or about 12 weeks, toachieve, in a group of such subjects, a success rate of at least about15%, about 25%, about 45%, or about 50%, respectively, wherein thesuccess rate is defined as the number of subjects achieving clear oralmost clear skin on the investor global assessment (IGA) scale aftertreatment with the pharmaceutical composition.

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2 weeks, toachieve, in a group of such subjects, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 40% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 25% after treatment with vehicle control.

In another exemplary embodiment, the mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 45% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 29% after treatment with vehicle control

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 4 weeks, toachieve, in a group of such subjects, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 55% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 35% after treatment with vehicle control.

In another exemplary embodiment, the mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 60% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 42% after treatment with vehicle control

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 8 weeks, toachieve, in a group of such subjects, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 60% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 35% after treatment with vehicle control.

In another exemplary embodiment, the mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 69% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 41% after treatment with vehicle control

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 12 weeks, toachieve, in a group of such subjects, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 65% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 35% after treatment with vehicle control.

In another exemplary embodiment, the mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 70% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 41% after treatment with vehicle control.

In other exemplary embodiments, the benzoyl peroxide is the sole activeingredient administered to the subject during the duration of theregimen.

In other exemplary embodiments, the pharmaceutical composition comprisesabout 2.5% w/w to about 10% w/w, and preferably about 5% w/w of benzoylperoxide.

In other exemplary embodiments, the benzoyl peroxide is in a formselected from solid, solution or suspension.

In other exemplary embodiments, the regimen is a first line therapy forthe treatment of rosacea in a subject 65 years and older.

In other exemplary embodiments, the rosacea is any oferythematotelengietatic, papulopustular, phymatous or ocular rosacea.

In other exemplary embodiments, the rosacea is moderate to severerosacea.

In other exemplary embodiments, the pharmaceutical composition is acream or an emulsion.

In other exemplary embodiments, the pharmaceutical composition is anextended release formulation.

In other exemplary embodiments, the extended-release effect is obtainedby encapsulation, microencapsulation, microspheres or coating.

In other exemplary embodiments, the benzoyl peroxide is encapsulated ormicroencapsulated.

In other exemplary embodiments, the benzoyl peroxide is included in amicrosphere or a coating.

Another exemplary embodiment is a pharmaceutical composition for use inthe treatment of severe rosacea in subjects aged 65 years and older. Thepharmaceutical composition comprises from about 1% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, and thepharmaceutical composition is applied once daily to a group of subjectsaged 65 years and older for a period of at least about 2 weeks, about 4weeks, about 8 weeks or about 12 weeks, to achieve, in a group of suchsubjects aged 65 years and older, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 40%, about 55%,about 60% or about 65%, respectively, compared to a mean percentagedecrease, from baseline, in the inflammatory lesions of about 25%, about35%, about 35% or about 35% after treatment with vehicle control. Inother exemplary embodiments, the mean percentage decrease, frombaseline, in the number of inflammatory lesions after treatment for aperiod of at least about 2 weeks, about 4 weeks, about 8 weeks or about12 weeks is about 45%, about 60%, about 69% or about 70%, respectively,compared to a mean percentage decrease, from baseline, in theinflammatory lesions of about 29%, about 42%, about 41% or about 41%,respectively, after treatment with vehicle control.

Details of other exemplary embodiments of the present disclosure will beincluded in the following detailed description and the accompanyingdrawings. It is appreciated that certain features of the exemplaryembodiments described in this application, which are, for clarity,described in the context of separate embodiments, can also be providedin combination in a single embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the disclosure and to see how it can be carriedout in practice, embodiments will now be described, by way ofnon-limiting examples only, with reference to the accompanying drawings,in which:

FIG. 1 is a bar graph of the results of Example 1 and ComparativeExample 1, showing the success rate of the treatment of in patients aged65 years and older based on the investigator global assessment (IGA)scale.

FIG. 2 is a bar graph of the results of Example 2 and ComparativeExample 2, showing the mean percentage decrease in the number ofinflammatory lesions in patients aged 65 years and older.

DETAILED DESCRIPTION

Multiple studies have been directed to the treatment of rosacea using apharmaceutical or dermatological active agent such as metronidazole,azelaic acid, sulfacetamide, brimonidine, ivermectin, permethrin andclindamycin, and with doxycycline, which is identified as the onlyFDA-approved treatment for rosacea (Oge et al., “Rosacea: Diagnosis andTreatment,” American Family Physician, v. 92(3), pp. 187-198 (2015); Gulet al., “A case of granulomatous rosacea successfully treated withpimecrolimus cream,” J. Derm. Treatment, 19, 313-315 (2008)).

Benzoyl peroxide (BPO) is generally identified as an anti-acne agent,used alone (U.S. Pat. No. 9,439,857; Wester et al., “Controlled releaseof benzoyl peroxide from a porous microsphere polymeric system canreduce topical irritancy,” J. Am. Acad. Derma. 24, 720-726 (1991);Sawleshwarkar, “Multicenter study to evaluate efficacy and irritationpotential of benzoyl peroxide 4% cream in hydrophase base (Brevoxyl) inacne vulgaris,” Ind. J. Derm. Vener. Lepro., 69(1), 19-22 (2003)) or incombination with a primary active such as avermectin (U.S.2011/0052515).

One such study includes a therapeutic regimen involving treatment ofacne rosacea in a group of patients in need of such treatment with 5%BPO-acetone gel for four weeks, followed by treatment of the same groupof patients with 10% BPO-acetone gel for an additional four weeks.(Montes et al., “Topical Treatment of Acne Rosacea with Benzoyl PeroxideAcetone Gel,” Therapeutics for the Clinician: New Reports on TreatmentModalities of Possible Interest to Patient-Caring Physicians, 32,185-190 (1983)). The Montes study showed a significantly better responseduring the five to eight weeks of treatment with 10% BPO-acetone gelcompared to the first four weeks of treatment with 5% BPO-acetone gel.Moreover, although Montes 1983 claims success in the treatment ofrosacea using a BPO-acetone gel, 25% of the patients in the study showedno improvement and 40% of the patients developed an irritation.Additionally, this study required increasing the amount of BPOadministered to the patients from 5% to 10% after week four. The resultsof the Montes 1983 study make it clear that BPO would not be suitablefor regular use in the treatment of rosacea, especially as a first linetreatment of rosacea.

Other studies show that, when used in the treatment of rosacea, BPO isgenerally combined with a primary active agent such as clindamycin(Breneman et al., “Double-blind, randomized, vehicle-controlled clinicaltrial of once-daily benzoyl peroxide/clindamycin topical gel in thetreatment of patients with severe rosacea,” Int. J Derm., 43, 381-387(2004); Gold et al., “Use of Benzoyl Peroxide/Clindamycin gel in theonce daily treatment of moderate rosacea,” J. Amer. Acad. Dermat.,52(3), sup., P25 (2004); Leyden et al., “Blind photographic review for adouble blind, multicenter, placebo-controlled study comparing BenzoylPeroxide/Clindamycin and placebo for the treatment of rosacea,” J. Amer.Acad. Dermat., 52(3), sup., P14 (2004); Goldgar et al., “TreatmentOptions for Acne Rosacea,” J Amer. Fam. Physician, 80(5), 461-468(2009)).

BPO is generally identified as only a possible second-line treatment ofrosacea following the use of another, different active. (Oge 2015, Table5; Goldgar 2009, “Key Recommendations for Practice”). Goldgar 2009, inparticular, recommends the use of BPO only as a tertiary therapy for thetreatment of rosacea.

When BPO was used as the sole active agent for the treatment of rosacea,lesions were found to be unresponsive. (Gul 2008).

These previous rosacea treatments with BPO alone or in combination withother agents, have been shown to have several drawbacks such asirritation and intolerance phenomena, especially when they areadministered for a prolonged period. (Crawford et al., “Rosacea: I.Etiology, pathogenesis, and subtype classification,” J. Am. Acad.Dermatol., 51, 327-341 (2004)). These treatments are only suppressiveand not curative, acting especially on the pustulous spasms occurringduring the inflammatory stage.

Such drawbacks associated with the treatment of rosacea involving theuse of BPO result in exclusion of BPO from standard rosacea treatmentmethods. For example, “A Review of the Current Modalities for theTreatment of Papulopustular Rosacea” identifies metronidazole,ivermectin and azelaic acid as topical therapies that were proveneffective for the treatment of rosacea. (McGregor et al., “A Review ofthe Current Modalities of the Treatment of Papulopustular Rosacea,”Dermatol. Clin. (2017)). While McGregor 2017 mentions alternatetherapies, such as sodium sulfacetanide/sulfur cream, clindamycin,tretinoin, calcineurin inhibitors and oral tretinoin, that may have someeffectiveness in the treatment of rosacea, notably, McGregor 2017 doesnot include, or even mention, BPO in the long list of possible treatmenttherapies described therein. The absence of BPO as a known treatment forrosacea is also evident in other studies. (Feaster et al., “Clinicaleffectiveness of novel rosacea therapies,” Current Op. Pharmacol., 46,14-18 (2019); Del Rosso et al., “Update on the Management of Rosaceafrom the American Acne & Rosacea Society (AARS); J. Clinical & AestheticDermat., 12 (6), 17-24 (2019)). The absence of BPO as a recognizedfirst-line treatment for rosacea is especially evident in Del Rosso,which is a well-known and respected authority on the treatment ofrosacea. The AARS review lists the Society's recommendation for rosaceatreatment, including topical metronidazole, topical azelaic acid, oraltetracyclines, ivermectin, topical alpha agonists, and oralisotretinoin, as well as “alternative therapies,” such assulfacetamide/sulfur, calcineurin inhibitors, retinoids, and permethrin.(See e.g., Table 1 of the AARS review.) BPO is not mentioned in the AARSreview either as a leading, or even an alternative, therapeutic agentfor the treatment of rosacea.

Considering the chronic nature of rosacea, there is a need for earlyonset of action, and a prolonged use and/or treatment of the disease,its symptoms and associated conditions, in a safe and effective manner.Thus, there exists a need for compositions that show early onset ofaction, and improved efficacy in the treatment of rosacea, that impartgreater tolerance to the active principles and that reduce,substantially minimize or do not have the side effects described in theprior art.

Advantages and features of the present disclosure, and methods foraccomplishing the same will be more clearly understood from exemplaryembodiments described below with reference to any accompanying drawingsand figures. However, the present disclosure is not limited to thefollowing exemplary embodiments and can be implemented in variousdifferent forms. The exemplary embodiments are provided only to providesufficient disclosure of the present discoveries and to fully provide aperson having ordinary skill in the art to which the present disclosurepertains within the technical field, and the present disclosure will bedefined by any appended claims and combinations thereof.

As used herein, like reference numerals generally denote like elementsthroughout the present specification. Further, in the followingdescription, a detailed explanation of well-known related technologiescan be omitted to avoid unnecessarily obscuring the subject matter ofthe present disclosure.

As used herein, terms such as “including” and “having” are generallyintended to allow other components to be included unless the terms areused in conjunction with the term “only.”

As used herein, the term “topical use” is meant to encompass the topicaladministration of an exemplary composition by formulating saidcomposition in any way known in the art, or in formulations disclosedherein, which are compatible with the skin, mucous membranes and/or theinteguments.

As used herein, the term “treating” or “treatment” includes curing acondition, treating a condition, preventing or substantially preventinga condition, treating symptoms of a condition, curing symptoms of acondition, ameliorating, reducing and/or minimizing symptoms of acondition, treating effects of a condition, ameliorating, reducingand/or minimizing effects of a condition, and preventing and/orsubstantially preventing results of a condition.

As used herein, the term “first-line therapy” or “first-line treatment”means a therapy or treatment for which its label does not include arequirement or recommendation that said therapy or treatment should beused only after other therapies or treatments were shown to beunsatisfactory or unsuccessful. It can also include a therapy and/ortreatment wherein no other actives (beyond the main active) areadministered to the individual subject in need.

As used herein, the term “success rate” corresponds to a percentageincrease in the number of subjects achieving clear or almost clear skinon the investigator global assessment (IGA) scale after treatment withthe pharmaceutical composition.

As used herein, the term “early onset” or “early onset of action” meansachieving a desired result and/or effect at a point in time that isearlier or even much early than achieved using a vehicle or other,conventional treatment approach. For example, it can mean achieving adesired result and/or effect no later than about 8 weeks from initialtreatment, preferably no later than about 4 weeks from initialtreatment, and more preferably no later than about 2 weeks from initialtreatment.

As used herein, the term “pharmaceutical composition” refers to acomposition comprising one or more active ingredients with othercomponents such as, for example, pharmaceutically acceptable ingredientsand/or excipients. The purpose of a pharmaceutical composition is tofacilitate administration of an active ingredient to a subject.

As used herein, the terms “pharmaceutically active agent” or “activeagent” or “active pharmaceutical ingredient” are interchangeable andmean the ingredient is a pharmaceutical drug, which is biologically-and/or chemically-active and is regulatory-approved or approvable assuch.

As used herein, the term “ingredient” refers to a pharmaceuticallyacceptable ingredient, which is included or is amenable to be includedin The FDA's Inactive Ingredient (IIG) database. Inactive ingredientscan sometimes exhibit some therapeutic effects, although they are notdrugs.

As used herein, the term “adverse events values” refers to an averagepercentage of subjects that experience any adverse events associatedwith the treatment of rosacea with a composition described and/orclaimed herein (usually on a surface of the skin of a subject treatedwith a composition described and/or claimed herein). A non-limiting listof such adverse events includes: irritation, dryness, scaling, itchingpurities, burning, stinging, combinations thereof and the like.

As used herein, the term “inflammatory lesion” refers to papules andpustules present on the skin of a patient, and does not include nodulesand cysts.

As used herein, the term “papule” refers to a solid, elevatedinflammatory lesion equal to or less than about 5 mm in diameter.

As used herein, the term “pustule” refers to an elevated inflammatory,pus-containing lesion equal to or less than about 5 mm in diameter.

As used herein, the term “nodule” and/or “cyst” refers to palpable solidinflammatory lesion, greater than about 5 mm in diameter. The noduleand/or cyst may have depth but does not necessarily include elevation.

Whenever a numerical range is indicated herewith, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicated number and asecond indicated number and “ranging/ranges from” a first indicatednumber “to” a second indicated number are used herein interchangeableand are meant to include the first and second indicated numbers and allfractional and integral numerals therebetween.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “10 μm” is intended to mean“about 10 μm.”

As used herein, numbers and/or numerical ranges preceded by the term“about” should not be considered to be limited to the recited range.Rather, numbers and/or numerical ranges preceded by the term “about”should be understood to include a range accepted by those skilled in theart for any given element in formations according to the subjectinvention.

As used herein, when a numerical value is preceded by the term “about,”the term “about” is intended to indicate +/−10%.

As used herein, the singular form “a,” “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” can include a pluralityof compounds, including combinations and/or mixtures thereof.

As used herein, the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, technical and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

It is appreciated that certain features of the exemplary embodimentsdescribed herein, which are, for clarity, described in the context ofseparate embodiments, can also be provided in combination in a singleembodiment. Conversely, various features of the exemplary embodiments,which are, for brevity, described in the context of a single embodiment,can also be provided separately or in any suitable sub-combination or assuitable in any other described embodiment. Certain features describedin the context of various embodiments are not to be considered essentialfeatures of those embodiments, unless the embodiment is inoperativewithout those elements.

An exemplary embodiment of this application is a regimen for thetherapeutic treatment of rosacea in subjects aged 65 years and older,the regimen comprising topically applying to the skin of a subject aged65 years and older in need of said treatment a pharmaceuticalcomposition, the pharmaceutical composition comprising about 1% w/w toabout 10% w/w benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is applied oncedaily for a period of at least about 2 weeks, to achieve, in a group ofsuch subjects, a success rate of at least about 15%, wherein the successrate is defined as the number of subjects achieving clear or almostclear skin on the investor global assessment (IGA) scale after treatmentwith the pharmaceutical composition.

In another exemplary embodiment, the success rate after about 2 weeks oftreatment is about 18%.

In another exemplary embodiment, the success rate of said regimen aftertreatment for about 2 weeks is at least about 10% greater than a successrate achieved by a vehicle control.

Another exemplary embodiment of this application is a regimen for thetherapeutic treatment of rosacea in a subject 65 years and older, theregimen comprising topically applying to the skin of a subject aged 65years and older in need of said treatment a pharmaceutical composition,the pharmaceutical composition comprising about 1% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, wherein saidpharmaceutical composition is applied once daily for a period of atleast about 4 weeks, to achieve, in a group of such subjects, a successrate of at least about 25%, wherein the success rate is defined as thenumber of subjects achieving clear or almost clear skin on the investorglobal assessment (IGA) scale after treatment with the pharmaceuticalcomposition.

In another exemplary embodiment, the success rate after about 4 weeks oftreatment is at least about 29%.

In another exemplary embodiment, the success rate of said regimen aftertreatment for about 4 weeks is at least about 2% greater than a successrate achieved by a vehicle control.

Another exemplary embodiment of this application is a regimen for thetherapeutic treatment of rosacea in a subject aged 65 years and older,the regimen comprising topically applying to the skin of the subjectaged 65 years and older in need of said treatment a pharmaceuticalcomposition, the pharmaceutical composition comprising about 1% w/w toabout 10% w/w benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is applied oncedaily for a period of at least about 8 weeks, to achieve, in a group ofsuch subjects, a success rate of at least about 45%, wherein the successrate is defined as the number of subjects achieving clear or almostclear skin on the investor global assessment (IGA) scale after treatmentwith the pharmaceutical composition.

In another exemplary embodiment, the success rate after about 8 weeks oftreatment is at least about 52%.

In another exemplary embodiment, the success rate of said regimen afterabout 8 weeks of treatment is at least about 20%, preferably at leastabout 27% greater than a success rate achieved by the vehicle control.

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 12 weeks, toachieve, in a group of such subjects, a success rate of at least about50%, wherein the success rate is defined as the number of subjectsachieving clear or almost clear skin on the investor global assessment(IGA) scale after treatment with the pharmaceutical composition.

In another exemplary embodiment, the success rate after treatment forabout 12 weeks is at least about 56%.

In another exemplary embodiment, the success rate of said regimen afterabout 12 weeks of treatment, is at least about 20%, preferably at leastabout 28% greater than the success rate achieved by the vehicle control.

Another exemplary embodiment is a pharmaceutical composition for use inthe treatment of severe rosacea, said pharmaceutical compositioncomprising from about 1% w/w to about 10% w/w benzoyl peroxide as anactive ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, and said pharmaceutical composition isapplied once daily for a period of at least about 2 weeks, about 4weeks, about 8 weeks or about 12 weeks, to achieve, in a group of suchsubjects, a success rate of at least about 15%, about 25%, about 45%, orabout 50%, respectively, wherein the success rate is defined as thenumber of subjects achieving clear or almost clear skin on the investorglobal assessment (IGA) scale after treatment with the pharmaceuticalcomposition.

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2 weeks, toachieve, in a group of such subjects, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 40% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 25% after treatment with vehicle control.

In another exemplary embodiment, the mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 45% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 29% after treatment with vehicle control

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 4 weeks, toachieve, in a group of such subjects, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 55% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 35% after treatment with vehicle control.

In another exemplary embodiment, the mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 60% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 42% after treatment with vehicle control

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 8 weeks, toachieve, in a group of such subjects, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 60% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 35% after treatment with vehicle control.

In another exemplary embodiment, the mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 69% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 41% after treatment with vehicle control

Another exemplary embodiment is a regimen for the therapeutic treatmentof rosacea in a subject aged 65 years and older, the regimen comprisingtopically applying to the skin of the subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 12 weeks, toachieve, in a group of such subjects, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 65% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 35% after treatment with vehicle control.

In another exemplary embodiment, the mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 70% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 41% after treatment with vehicle control.

In other exemplary embodiments, the benzoyl peroxide is the sole activeingredient administered to the subject during the duration of theregimen.

In other exemplary embodiments, the pharmaceutical composition comprisesabout 2.5% w/w to about 10% w/w of benzoyl peroxide, preferably about 3%to about 9%, about 4% to about 8%, and more preferably about 5% w/w ofbenzoyl peroxide.

In other exemplary embodiments, the benzoyl peroxide is selected fromsolid, solution or suspension form.

In other exemplary embodiments, the regimen is a first line therapy forthe treatment of rosacea in a subject 65 years and older.

In other exemplary embodiments, the rosacea is any one oferythematotelengietatic rosacea, papulopustular rosacea, phymatousrosacea or ocular rosacea.

In other exemplary embodiments, the rosacea is moderate to severerosacea, preferably severe rosacea.

In other exemplary embodiments, the pharmaceutical composition is acream or an emulsion.

In other exemplary embodiments, the pharmaceutical composition is anextended release formulation. The extended-release effect can beobtained by encapsulation, microencapsulation, microspheres or coating.The benzoyl peroxide can be encapsulated or microencapsulated, thebenzoyl peroxide can be included in a microsphere or a coating, and thelike.

In some further embodiments, the composition further comprises at leastone non pharmaceutical active additive selected from the groupconsisting of chelating agents, antioxidants, sunscreens, preservatives,fillers, electrolytes, humectants, dyes, mineral or organic acids orbases, fragrances, essential oils, moisturizers, vitamins, essentialfatty acids, sphingolipids, self-tanning compounds, calmatives andskin-protecting agents, pro-penetrating agents and gelling agents, or amixture and/or combination thereof.

In other embodiments, the composition is formulated into a topicallyapplicable, physiologically acceptable medium comprising of: (a) atleast one member selected from the group consisting of water, alcohols,oils, fatty substances and waxes; and (b) at least one additive selectedfrom the group consisting of chelating agents, antioxidants, sunscreens,preservatives, fillers, electrolytes, humectants, dyes, mineral acids,mineral bases, organic acids, organic bases, fragrances, essential oils,moisturizers, vitamins, essential fatty acids, sphingolipids,self-tanning compounds, calmatives, skin-protecting agents,pro-penetrating agents, gelling agents, emulsifiers, co-emulsifiers, andmixtures and/or combinations thereof.

In some embodiments, the composition is formulated as an emulsion(including an oil-in-water emulsion, a water-in-oil emulsion, multipleemulsions and microemulsions). In other embodiments, the composition isformulated as a cream.

Another exemplary embodiment is a pharmaceutical composition for use inthe treatment of severe rosacea in subjects aged 65 years and older. Thepharmaceutical composition comprises from about 1% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, and thepharmaceutical composition is applied once daily to a group of subjectsaged 65 years and older for a period of at least about 2 weeks, about 4weeks, about 8 weeks or about 12 weeks, to achieve, in a group of suchsubjects aged 65 years and older, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 40%, about 55%,about 60% or about 65%, respectively, compared to a mean percentagedecrease, from baseline, in the inflammatory lesions of about 25%, about35%, about 35% or about 35% after treatment with vehicle control. Inother exemplary embodiments, the mean percentage decrease, frombaseline, in the number of inflammatory lesions after treatment for aperiod of at least about 2 weeks, about 4 weeks, about 8 weeks or about12 weeks is about 45%, about 60%, about 69% or about 70%, respectively,compared to a mean percentage decrease, from baseline, in theinflammatory lesions of about 29%, about 42%, about 41% or about 41%,respectively, after treatment with vehicle control.

The compositions described in exemplary embodiments herein arepharmaceutical compositions, and especially dermatological compositions,which can be in any galenical form conventionally used for topicalapplication. By addition of a fatty or oily phase, they can also be inthe form of dispersions of the lotion or serum type, emulsions of liquidor semi-liquid consistency of the milk type obtained by dispersing afatty phase in an aqueous phase (O/W) or conversely (W/O), orsuspensions or emulsions of soft, semiliquid or solid consistency of thecream, gel or ointment type, or alternatively multiple emulsions (W/O/Wor O/W/O), microemulsions, microcapsules, microparticles and/orvesicular dispersions of ionic and/or nonionic type, and/or wax/aqueousphase dispersions. These compositions are formulated according to theusual methods.

In further embodiments, the composition comprises, as a singlepharmaceutical active agent, benzoyl peroxide in a solid form, fortopical use in the treatment of rosacea, is an oil in water emulsioncomprising a polyoxylstearate and a glycerylstearate. Various methodsfor the preparation of the BPO-containing compositions are described inU.S. Application Publication Nos. 2010/0016443, 2017/0281571 and2018/0147165 and U.S. Pat. No. 9,687,465.

In some embodiments, the ratio of said polyoxylstearate to saidglycerylstearate is in the range of about 0.1:10 to about 10:0.1.

In yet further embodiments, said polyoxylstearate is selected from thegroup consisting of Polyoxyl-8 stearate, Polyoxyl-20 stearate,Polyoxyl-40 stearate, Polyoxyl-100 stearate and combinations and/ormixtures thereof.

In further embodiments, said glycerylstearate is selected from the groupconsisting of glyceryl mono-stearate, glyceryl di-stearate andcombinations and/or mixtures thereof.

In other embodiments, said polyoxylstearate in said composition is inthe range of from about 0.1% w/w to about 30% w/w.

In further embodiments, the amount of said glycerylstearate in saidcomposition is in the range of from about 0.1% w/w to about 30% w/w.

In other embodiments, said composition further comprises at least onefatty alcohol.

In other embodiments, said at least one fatty alcohol is selected fromthe group consisting of octyl alcohol, 2-ethyl hexanol. nonyl alcohol,decyl alcohol, undecanol, dodecyl alcohol, tridecyl alcohol, tetradecylalcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol,heptadecyl alcohol, cetostearyl alcohol, stearyl alcohol, isostearylalcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol,elaidolinolenyl alcohol, ricinoleyl alcohol, nonadecyl alcohol,arachidyl alcohol, heneicosyl alcohol. behenyl alcohol, erucyl alcohol,lignoceryl alcohol, ceryl alcohol, montanyl alcohol, cluytyl alcohol,myricyl alcohol, melissyl alcohol, geddyl alcohol, cetearyl alcohol andcombinations and/or mixtures thereof.

In further embodiments, the amount of said at least one fatty alcohol insaid composition is in the range of from about 0.2% w/w to about 50%w/w.

In yet other embodiments, said composition further comprises apolyacrylic acid homopolymer or copolymer.

In other embodiments, said oil in said oil in water emulsion is selectedfrom the group consisting of paraffin oil, isopropyl myristate,caprylic/capric triglyceride, squalane, squalene, almond oil, castoroil, olive oil, jojoba oil, sunflower oil, soybean oil, grape seed oil,dimethicone, cyclomethicone and combinations and/or mixtures thereof.

In further embodiments, said oil in present in the composition in anamount in the range of from about 0.05% w/w to about 50% w/w.

In some embodiments, said water in said oil in water emulsion furthercomprises at least one water soluble humectant.

In other embodiments, said at least one water soluble humectant isselected from the group consisting of propylene glycol, glycerin,polyethylene glycol-X and combinations and/or mixtures thereof, where Xis in the range of from about 200 to about 10,000.

In some embodiments, the composition comprises said solid BPO in acontrolled and/or slowed release drug delivery system. In furtherembodiments, said controlled and/or slowed release drug delivery systemis an encapsulation in a microcapsule, wherein said solid BPO isembedded in said microcapsule. When referring to a “controlled and/orslowed release drug delivery system” it should be understood to relateto a delivery system (which in the present application is a topicaldelivery system) that enables the release of the pharmaceutical activeagent in predetermined amounts over a specified period. In someembodiments, said system is a core-shell system of a microcapsule and/ora porous matrix structure, such as, for example, a microsponge. The term“embedded” should be understood to encompass an inert system thatprovides a barrier between the pharmaceutical active agent, i.e. BPO,and its surrounding environment in the composition. In some embodiments,said agent is entrapped and/or encapsulated in said controlled releasesystem.

In some embodiments, said core of said microcapsule comprises orconsists of said solid BPO.

In some further embodiments, said microcapsules are a core shellmicrocapsule. The shell comprises at least one inorganic polymer. Insome other embodiments, said inorganic polymer of said shell is a metaloxide or semi-metal oxide shell (layer).

In some embodiments, said microcapsule comprises a metal oxide orsemi-metal oxide coating or layer (shell) and a core comprising orconsisting of solid BPO.

In some embodiments, said microcapsule comprises a metal oxide orsemi-metal oxide coating or layer (shell) and a core comprising solidBPO is prepared by a process comprising the steps of:

-   -   (a) contacting a solid BPO particulate matter with an ionic        additive and an aqueous medium to obtain a dispersion of said        particulate matter having positive charges on its surface;    -   (b) subjecting the particulate matter to a coating procedure        comprising precipitating a metal oxide salt onto the surface of        the particulate matter to form a metal oxide layer thereon        thereby to obtain particulate matter coated by a metal oxide        coating layer;    -   (c) repeating step (b) at least 4 more times: and    -   (d) aging said coating layer.

As used herein, the term “solid BPO particulate matter” refers to asolid BPO having solubility in water of less than about 1% w/w,typically less than about 0.5% and at times less than about 0.1% w/w atroom temperature (about 20° C.). The “solid BPO particulate matter”constitutes the “core” of the particles obtained by the process. Thesolid BPO particulate matter, is, in some embodiments, in such a stateof subdivision that it can be suspended in water, e.g., in the form of afinely-divided powder having a D₉₀ (see definition below), in someembodiments in the range of from about 0.3 to about 50 microns. Such aparticulate matter can be readily suspended in an aqueous systems bystirring, with or without the aid of a surfactant.

The terms “solid BPO particulate matter” and “particulate matter” willbe used interchangeably.

In the present application, the terms “layer”, “coating” or “shell” andsimilar terms, refer to a layer of metal oxide or semi-metal oxideformed around a particle or particulate matter. The layer or coatingneed not always be complete or uniform and need not necessarily lead tocomplete coverage of the particulate matter or particle surface. It isappreciated that upon repetition of the coating steps as the coatingprocess proceeds a more uniform coating and more complete coverage ofthe particulate matter is obtained.

The term “dispersion,” as used herein, in step (a) of the process refersto a solid dispersion of the particulate matter in the aqueous medium.Step (a) of the process can further comprise reducing the particle sizeof the particulate matter to the desired particle size, for example, bymilling or homogenization.

The core (i.e., solid, BPO particulate matter) can be of any shape, forexample, rod-like, plate-like, ellipsoidal, cubic, spherical shape,combinations thereof and the like.

Reference to the size of particles will be made through their D₉₀, whichmeans that about 90% of the particles have the stated dimension or less(measured by volume). Thus, for example, for spherical particles statedto have a diameter of about 10 micrometer (“microns”), this means thatthe particles have a D₉₀ of about 10 microns. The D₉₀ can be measured bylaser diffraction. For particles having a shape other than spheres, theD₉₀ refers to the mean average of the diameter of a plurality ofparticles.

In the case of cores having a spherical shape, the D₉₀ can be in therange of from about 0.3 to 90 microns, in some embodiments from about0.3 to about 50 microns, in some other embodiments from about 1 to about50 microns, in some further embodiments from about 5 to about 30microns. As used herein, the phrase “D₉₀ can be in the range of fromabout 0.3 microns to about 90 microns” means about 90% by volume of theparticles (in this case the particle's core) can be less than or equalto a value in the range of from about 0.3 microns to about 90 microns.

For generally cubic-shaped cores or cores having a shape resembling thatof a cube, the mean size of a side can be in the range of from about 0.3to about 80 microns, in some embodiments from about 0.3 to about 40microns, in some further embodiments from about 0.8 to about 40 microns,in some further embodiments from about 4 to about 15 microns.

For rod-like shaped, ellipsoidal-shaped and plate-like shaped cores, thelargest dimension (that of the longest axis) is typically in the rangeof from about 10 to about 100 microns, in some embodiments from about 15to about 50 microns; and the smallest dimension is typically in therange of from about 0.5 to about 20 microns, in some further embodimentsfrom about 2 to about 10 microns.

As used herein, unless otherwise indicated, the term “particle” refersto the metal oxide or semi-metal oxide coated particulate matter.

It is appreciated that some of the particles obtained by the process canat times be formed from two or more original particles of the solid BPOparticulate and can accordingly include at times more than one core,such cores being separated from each other by a metal oxide region.

The weight of the solid BPO particulate (core material) based on thetotal weight of the particle can be in the range of from about 99% w/wto about 50% w/w, in some embodiments in the range of from about 97% w/wto about 50% w/w. The core material can be in a crystalline form,amorphous form, or combination thereof. The core material can be acosmetic, pharmaceutical or an agrochemical active ingredient.

Exemplary Embodiments

BPO-containing compositions were prepared following the variouspreparation methods described in U.S. Application Publication Nos.2010/0016443, 2017/0281571 and 2018/0147165 and U.S. Pat. No. 9,687,465,the contents of which are incorporated herein, by reference, in theirentirety.

Description: A randomized, double-blind, multi-center, parallel group,active- and vehicle-controlled study of encapsulated 5% benzoyl peroxidecream (E-BPO) and vehicle cream was performed to assess the efficacy andsafety of E-BPO compared to vehicle. Study duration was 12 weeks andincluded approximately 350 male and female patients afflicted withpapulopustular rosacea. 71 patients (about 20%) were at least 65 yearsof age.

Patients were admitted into the study after meeting allinclusion/exclusion criteria, including a clinical diagnosis of rosacea.Subjects with moderate to severe rosacea who were appropriate forsystemic treatment were counseled regarding their treatment options bythe Principal Investigator. At each visit, a 5-point IGA scale ofrosacea and inflammatory lesion counts were performed and recorded.

Dosing: Patients were randomly organized in a 2:1 ratio to the studyproduct or vehicle treatment group, respectively. Patients applied thestudy product once daily for 12 weeks on the face in a thin layer toprovide even distribution.

Clinical and Safety Evaluations were performed at Baseline and Weeks 2,4, 8 and 12.

Summary of Investigator Global Assessment:

The success rate of the treatment of rosacea (defined as a 2-gradeimprovement in the IGA relative to Baseline at Weeks 2, 4, 7 and 12,with an IGA of Clear or Almost Clear) in patients aged 65 years andolder are shown in Table 1 and FIG. 1 . For the data in Table 1,multiple imputation (MCMC) were used to impute missing values, and thepercentage values for Weeks 2, 4, 8, and 12 represent average values,obtained from averaging the summary statistics generated from eachimputed dataset.

The mean percentage of patients aged 65 years and older achieving aClear to Almost Clear grade after 5% E-BPO cream were: about 18% (week2), about 29% (week 4), about 52% (week 8) and about 56% (week 12). Theresults also show that the success rate (which is the difference betweenthe drug and vehicle) after treatment with 5% E-BPO cream is at least10% (week 2), about 2% (week 4), about 27% (week 8) and about 28% (week12) greater than the success rate achieved after treatment with vehiclealone for the corresponding amount of time. The results are shown inFIG. 1 .

As seen from these results, topical application of BPO is highlyeffective in a treatment regime for the treatment of rosacea in patientsaged 65 years and older. These results show the unexpectedly superiorsuccess rate after treatment with BPO compared to vehicle alone. Afterabout 8 weeks of treatment, 25% more patients treated with BPOdemonstrated Clear and Almost Clear grade compared to patients treatedwith vehicle alone.

TABLE 1 Percentage of Patients with Clear or Almost Clear AssessmentExample 2 Comparative Example 2 (5% E-BPO; N = 48) (Vehicle Alone; N =23) Week 2 18.8 8.7 Week 4 29.2 27.0 Week 8 52.1 25.2 Week 12 56.3 27.8

Evaluation of Inflammatory Lesion Counts:

The mean percentage decrease in the number of inflammatory lesions in agroup of patients aged 65 years and older after treatment with 5% E-BPOand vehicle alone, respectively, at Baseline and Weeks 2, 4, 8 and 12are shown in Table 2 and FIG. 2 . For the data in Table 2, multipleimputation (MCMC) were used to impute missing values, the percentagevalues for Weeks 2, 4, 8, and 12 represent average values, obtained fromaveraging the summary statistics generated from each imputed dataset,and negative values represent decrease from Baseline.

The mean percentage decrease, from Baseline, of inflammatory lesioncounts in patients aged 65 years and older is: about 45% (week 2), about60% (week 4), about 69% (week 8) and about 70% (week 12) after treatmentwith E-BPO compared to about 29% (week 2), about 42% (week 4), about 41%(week 8) and about 41% (week 12). The unexpectedly superior reduction ininflammatory lesion count after treatment with BPO is about 15% to about30% higher than the reduction in inflammatory lesion counts observedafter treatment with vehicle alone.

TABLE 2 Example 1A Comparative Example 1A (5% E-BPO) (Vehicle Alone)Mean Mean Inflammatory Percent Inflammatory Percent Lesion Count Changefrom Lesion Count Change from (N = 48) Baseline (%) (N = 23) Baseline(%) Baseline 24.1 — 22.0 — Week 2 13.3 −44.85 15.9 −28.58 Week 4 9.8−60.3 14.0 −41.67 Week 8 7.8 −69.34 14.7 −40.82 Week 12 7.6 −70.42 14.4−41.05

The above-discussed results demonstrate the unexpected superiority ofthe benzoyl peroxide composition described in this application in thetreatment of rosacea in patients aged 65 years and older.

Although the exemplary embodiments of the present disclosure have beendescribed in detail with reference to the accompanying examples anddrawings, the present disclosure is not limited thereto and can beembodied in many different forms without departing from the technicalconcept of the present disclosure. Therefore, the exemplary embodimentsof the present disclosure are provided for illustrative purposes onlyand are not intended to limit the technical concept of the presentdisclosure. The protective scope of the present disclosure should beconstrued based on any appended claims and combinations thereof, and allthe technical concepts in the equivalent scope thereof should beconstrued as falling within the scope of the present disclosure. Asvarious changes could be made in the above methods and compositionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in a limiting sense. Other embodiments within thescope of the claims herein will be apparent to one skilled in the artfrom consideration of the specification or practice of the exemplaryembodiments disclosed herein. It is intended that the specification beconsidered exemplary only, with the scope and spirit of the describedsubject matter being indicated by the claims.

What is claimed is:
 1. A regimen for the therapeutic treatment ofrosacea in subjects aged 65 years and older, the regimen comprisingtopically applying to the skin of a subject aged 65 years and older inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 2.5% w/w to about 10% w/w benzoyl peroxideas an active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2 weeks, toachieve, in a group of such subjects, a success rate of at least about15%, wherein the success rate is defined as the number of subjectsachieving clear or almost clear skin on the investor global assessment(IGA) scale after treatment with the pharmaceutical composition.
 2. Theregimen of claim 1, wherein the success rate of said regimen is at leastabout 10% greater than a success rate achieved by a vehicle control. 3.The regimen of claim 1, wherein said pharmaceutical composition isapplied once daily for a period of at least about 4 weeks, to achieve,in a group of such subjects, a success rate of at least about 25%,wherein the success rate is defined as the number of subjects achievingclear or almost clear skin on the investor global assessment (IGA) scaleafter treatment with the pharmaceutical composition.
 4. The regimen ofclaim 3, wherein the success rate of said regimen is at least about 2%greater than a success rate achieved by a vehicle control.
 5. Theregimen of claim 1, wherein said pharmaceutical composition is appliedonce daily for a period of at least about 8 weeks, to achieve, in agroup of such subjects, a success rate of at least about 45%, whereinthe success rate is defined as the number of subjects achieving clear oralmost clear skin on the investor global assessment (IGA) scale aftertreatment with the pharmaceutical composition.
 6. The regimen of claim5, wherein the success rate of said regimen is at least about 27%greater than a success rate achieved by the vehicle control.
 7. Theregimen of claim 1, wherein said pharmaceutical composition is appliedonce daily for a period of at least about 12 weeks, to achieve, in agroup of such subjects, a success rate of at least about 50%, whereinthe success rate is defined as the number of subjects achieving clear oralmost clear skin on the investor global assessment (IGA) scale aftertreatment with the pharmaceutical composition.
 8. The regimen of claim7, wherein the success rate of said regimen is at least about 28%greater than the success rate achieved by the vehicle control.
 9. Theregimen of claim 1, wherein the benzoyl peroxide is the sole activeingredient administered to the subject during the duration of theregimen.
 10. The regimen of claim 1, wherein the pharmaceuticalcomposition comprises about 5% w/w of benzoyl peroxide.
 11. The regimenof claim 1, wherein the benzoyl peroxide is in a form selected fromsolid, solution or suspension.
 12. The regimen of claim 1, wherein theregimen is a first line therapy for the treatment of rosacea, whereinthe rosacea is any of erythematotelengietatic, papulopustular, phymatousor ocular rosacea.
 13. The regimen of claim 1, wherein saidpharmaceutical composition is a cream or an emulsion.
 14. The regimen ofclaim 1, wherein said pharmaceutical composition is an extended releaseformulation, wherein the extended-release effect is obtained byencapsulation, microencapsulation, microspheres or coating.
 15. Apharmaceutical composition for use in the treatment of severe rosacea ina subject aged 65 years and older, said pharmaceutical compositioncomprising from about 2.5% w/w to about 10% w/w benzoyl peroxide as anactive ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, and said pharmaceutical composition isapplied once daily for a period of at least about 2 weeks, 4 weeks, 8weeks or 12 weeks, to achieve, in a group of such subjects, a successrate of at least about 15%, about 25%, about 45%, about 50%,respectively, wherein the success rate is defined as the number ofsubjects achieving clear or almost clear skin on the investor globalassessment (IGA) scale after treatment with the pharmaceuticalcomposition.
 16. The pharmaceutical composition of claim 15, whereinsaid pharmaceutical composition comprises about 5.0% w/w benzoylperoxide.
 17. A regimen for the therapeutic treatment of rosacea in asubject aged 65 years and older, the regimen comprising topicallyapplying to the skin of the subject aged 65 years and older in need ofsaid treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 2.5% w/w to about 10% w/w benzoyl peroxideas an active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2 weeks, toachieve, in a group of such subjects, a mean percentage decrease, frombaseline, in the number of inflammatory lesions of about 40% compared toa mean percentage decrease, from baseline, in the inflammatory lesionsof about 25% after treatment with vehicle control.
 18. The regimen ofclaim 17, wherein said pharmaceutical composition is applied once dailyfor a period of at least about 4 weeks, to achieve, in a group of suchsubjects, a mean percentage decrease, from baseline, in the number ofinflammatory lesions of about 55% compared to a mean percentagedecrease, from baseline, in the inflammatory lesions of about 35% aftertreatment with vehicle control.
 19. The regimen of claim 17, whereinsaid pharmaceutical composition is applied once daily for a period of atleast about 8 weeks, to achieve, in a group of such subjects, a meanpercentage decrease, from baseline, in the number of inflammatorylesions of about 60% compared to a mean percentage decrease, frombaseline, in the inflammatory lesions of about 35% after treatment withvehicle control.
 20. The regimen of claim 17, wherein saidpharmaceutical composition is applied once daily for a period of atleast about 12 weeks, to achieve, in a group of such subjects, a meanpercentage decrease, from baseline, in the number of inflammatorylesions of about 65% compared to a mean percentage decrease, frombaseline, in the inflammatory lesions of about 35% after treatment withvehicle control.
 21. The regimen of claim 17, wherein the benzoylperoxide is the sole active ingredient administered to the subjectduring the duration of the regimen.
 22. The regimen of claim 17, whereinthe pharmaceutical composition comprises about 5% w/w of benzoylperoxide.
 23. The regimen of claim 17, wherein the benzoyl peroxide isin a form selected from solid, solution or suspension.
 24. The regimenof claim 17, wherein the regimen is a first line therapy for thetreatment of rosacea, wherein the rosacea is any oferythematotelengietatic, papulopustular, phymatous or ocular rosacea.25. The regimen of claim 17, wherein said pharmaceutical composition isa cream or an emulsion.
 26. The regimen of claim 17, wherein saidpharmaceutical composition is an extended release formulation, whereinthe extended-release effect is obtained by encapsulation,microencapsulation, microspheres or coating.
 27. A pharmaceuticalcomposition for use in the treatment of severe rosacea in subjects aged65 years and older, said pharmaceutical composition comprising fromabout 2.5% w/w to about 10% w/w benzoyl peroxide as an activeingredient, and a pharmaceutically acceptable carrier or excipient,wherein the benzoyl peroxide is the only active ingredient in saidpharmaceutical composition, and said pharmaceutical composition isapplied once daily to a group of subjects aged 65 years and older for aperiod of at least about 2 weeks, about 4 weeks, about 8 weeks or about12 weeks, to achieve, in a group of such subjects aged 65 years andolder, a mean percentage decrease, from baseline, in the number ofinflammatory lesions of about 40%, about 55%, about 60% or about 65%,respectively, compared to a mean percentage decrease, from baseline, inthe inflammatory lesions of about 25%, about 35%, about 35% or about35%, respectively, after treatment with vehicle control.
 28. Thepharmaceutical composition of claim 27, wherein the mean percentagedecrease, from baseline, in the number of inflammatory lesions aftertreatment for a period of at least about 2 weeks, about 4 weeks, about 8weeks or about 12 weeks is about 45%, about 60%, about 69% or about 70%,respectively, compared to a mean percentage decrease, from baseline, inthe inflammatory lesions of about 29%, about 42%, about 41% or about41%, respectively, after treatment with vehicle control.
 29. Thepharmaceutical composition of claim 27, wherein said pharmaceuticalcomposition comprises about 5.0% w/w benzoyl peroxide.
 30. The regimenof claim 1, wherein said pharmaceutical composition comprises a fattyphase and/or an oily phase.
 31. The pharmaceutical composition of claim15, wherein said pharmaceutical composition comprises a fatty phaseand/or an oily phase.
 32. The regimen of claim 17, wherein saidpharmaceutical composition comprises a fatty phase and/or an oily phase.33. The regimen of claim 27, wherein said pharmaceutical compositioncomprises a fatty phase and/or an oily phase.